X-ROS signaling in the heart and skeletal muscle: Stretch-dependent local ROS regulates [Ca2+]i

X-ROS signaling is a novel redox signaling pathway that links mechanical stress to changes in [Ca2+](i). This pathway is activated rapidly and locally within a muscle cell under physiological conditions, but can also contribute to Ca2+-dependent arrhythmia in the heart and to the dystrophic phenotype in the heart and skeletal muscle. Upon physiologic cellular stretch, microtubules serve as mechanotransducers to activate NADPH oxidase 2 in the transverse tubules and sarcolemmal membranes to produce reactive oxygen species (ROS). In the heart, the ROS acts locally to activate ryanodine receptor Ca2+ release channels in the junctional sarcoplasmic reticulum, increasing the Ca2+ spark rate and tuning excitation-contraction coupling. In the skeletal muscle, where Ca2+ sparks are not normally observed, the X-ROS signaling process is muted. However in muscular dystrophies, such as Duchenne Muscular Dystrophy and dysferlinopathy, X-ROS signaling operates at a high level and contributes to myopathy. Importantly, Ca2+ permeable stretch-activated channels are activated by X-ROS and contribute to skeletal muscle pathology. Here we review X-ROS signaling and mechanotransduction in striated muscle, and highlight important questions to drive future work on stretch-dependent signaling. We conclude that X-ROS provides an exciting mechanism for the mechanical control of redox and Ca2+ signaling, but much work is needed to establish its contribution to physiologic and pathophysiologic processes in diverse cell systems. This article is part of a Special Issue entitled Calcium Signaling in Heart. (C) 2012 Elsevier Ltd. All rights reserved.